Summary: Chronic kidney disease (CKD) is a public health epidemic that affects millions. It is associated with a dramatically increased risk of cardiovascular mortality that is associated with the abnormal phosphate, calcitriol (1,25-D) and parathyroid metabolism that constitute secondary hyperparathyroidism (sHPT). Although factors that exacerbate sHPT in stage 5 CKD (US prevalence ~300,000) are well defined, much less is known about factors that initiate its pathogenesis in stages 3-4 (US prevalence ~8,000,000). Fibroblast growth factor-23 (FGF-23) maintains normal serum phosphate levels by augmenting phosphaturia and inhibiting 1,25-D synthesis. We hypothesize that through its reversible inhibition of 1,25-D synthesis, xaggerated FGF-23 secretion may be a root cause of sHPT in CKD that is modifiable in clinical practice. An experienced investigative team will use a multi-disciplinary approach to examine the role of FGF-23 in sHPT across the spectrum of CKD. We will perform in-depth physiological studies on the GCRC to study FGF-23 physiology in detail in the fasting and postprandial states among healthy volunteers and CKD subjects. We will examine the clinical utility of several phosphorous reduction strategies in a randomized controlled trial of "normophosphatemic" CKD patients. The aim is to establish the pathogenic primacy of phosphate loading, acting via increased FGF-23, in the development of sHPT even in the absence of hyperphosphatemia. Next, we will examine FGF-23 as a novel biomarker of overall phosphorous exposure in stage 5 CKD. We will test whether FGF-23 excess is associated with increased mortality on dialysis within ArMORR, a prospective cohort of 15,000 incident hemodialysis patients. All studies are IRB-approved and preliminary data support our hypotheses. Relevance: The overall purpose of this research application is to establish the importance of assessing and modifying net phosphorous exposure, marked by changes in FGF-23, in an effort to improve the dismal outcomes in CKD. Detailed examination of our hypotheses will provide novel insight into the role of FGF-23 in normal renal physiology and in CKD, and suggest novel therapeutic paradigms for ameliorating sHPT and perhaps, cardiovascular disease in CKD. The results will be of immediate clinical relevance for the millions of normophosphatemic CKD patients who outnumber hyperphosphatemic patients at least 10-fold but for whom current guidelines do not recommend aggressive phosphate reduction strategies.